U.S. patent application number 16/369251 was filed with the patent office on 2019-10-17 for acidifying coatings and disintegration-resistant substrates coated therewith.
This patent application is currently assigned to BPSI Holdings LLC. The applicant listed for this patent is BPSI Holdings LLC. Invention is credited to Raxitkumar Y. Mehta, George Reyes, Jason Teckoe, Daniel To.
Application Number | 20190314286 16/369251 |
Document ID | / |
Family ID | 68161045 |
Filed Date | 2019-10-17 |
United States Patent
Application |
20190314286 |
Kind Code |
A1 |
Mehta; Raxitkumar Y. ; et
al. |
October 17, 2019 |
ACIDIFYING COATINGS AND DISINTEGRATION-RESISTANT SUBSTRATES COATED
THEREWITH
Abstract
The present invention includes acidifying film coating
compositions containing a polymer and an acidic component for use
on orally-ingestible substrates such as tablets and the like. The
acidifying coating compositions can be applied as an aqueous
dispersion to an enteric-coated substrate to increase the
disintegration resistance to aqueous media of up to pH 5.0. In
preferred aspects, the acidic component is citric acid, lactic
acid, stearic acid or mixtures thereof. Methods of preparing the
dry film coatings, methods of preparing corresponding aqueous
dispersions, methods of applying the coatings to substrates and the
coated substrates themselves are also disclosed.
Inventors: |
Mehta; Raxitkumar Y.;
(Lansdale, PA) ; Reyes; George; (Perkiomenville,
PA) ; Teckoe; Jason; (Dartford, GB) ; To;
Daniel; (Maple Glen, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BPSI Holdings LLC |
Wilmington |
DE |
US |
|
|
Assignee: |
BPSI Holdings LLC
Wilmington
DE
|
Family ID: |
68161045 |
Appl. No.: |
16/369251 |
Filed: |
March 29, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62656611 |
Apr 12, 2018 |
|
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|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C08K 2003/2241 20130101;
A61K 9/2853 20130101; C09D 101/284 20130101; A61K 9/2846 20130101;
C09D 101/286 20130101; C09D 7/63 20180101; C08L 3/02 20130101; C09D
101/284 20130101; C09D 101/284 20130101; C08K 5/09 20130101; C08K
5/092 20130101; A61K 9/2893 20130101; C08L 3/02 20130101; A61K
9/2866 20130101; C08K 5/09 20130101; C08L 1/284 20130101; C08L 1/04
20130101; C08L 1/284 20130101; C08K 5/09 20130101; C08L 1/04
20130101; C08K 5/51 20130101; A61K 9/2886 20130101; A61K 9/2013
20130101 |
International
Class: |
A61K 9/28 20060101
A61K009/28; A61K 9/20 20060101 A61K009/20 |
Claims
1. A dry, acidifying coating composition comprising a polymer and
an acidic component.
2. The composition of claim 1, wherein the polymer is selected from
the group consisting of hypromellose (hydroxypropylmethyl cellulose
or HPMC), hydroxypropyl cellulose (HPC), sodium carboxymethyl
cellulose, polyvinyl alcohol (PVA), polyvinyl alcohol-polyethylene
glycol graft copolymer, other copolymers based on PVA and mixtures
thereof.
3. The composition of claim 1, wherein the acidic component
comprises ionizable hydrogen ions.
4. The composition of claim 3, wherein the acidic component is
selected from the group of citric acid, lactic acid, stearic acid
and mixtures thereof.
5. The composition of claim 1, wherein the polymer is about 10-90%
by weight of the composition.
6. The composition of claim 5, wherein the polymer is about 25-85%
by weight of the composition.
7. The composition of claim 6, wherein the polymer is about 30-80%
by weight of the composition.
8. The composition of claim 1, wherein the acidic component is
about 5-50% by weight of the composition.
9. The composition of claim 8, wherein the acidic component is
about 8-45% by weight of the composition.
10. The composition of claim 1, further comprising one or more of a
plasticizer, detackifier, pigment or surfactant.
11. A composition of claim 10, wherein the polymer is present in an
amount of from about 25 to about 85% by weight of the composition;
the amount of the acidic component is present in an amount of from
about 8 to about 45% by weight of the composition; the plasticizer
is present in an amount of from about 2 to about 18% by weight of
the polymer; and the detackifier is present in an amount of from
about 5 to about 45% by weight of the composition.
12. An aqueous dispersion comprising the composition of claim 1 and
water.
13. The aqueous dispersion of claim 12, further comprising one or
more of a plasticizer, a detackifier, a pigment and a surfactant,
added as part of the dry coating composition.
14. The aqueous dispersion of claim 12, further comprising one or
more of a plasticizer, a detackifier, a pigment and a surfactant,
added separately to the aqueous dispersion.
15. An orally-ingestible substrate coated with the aqueous
dispersion of claim 12.
16. The orally-ingestible substrate of claim 15, further comprising
an enteric coating beneath the acidifying coating.
17. The orally-ingestible substrate of claim 16, further comprising
a subcoat between the orally-ingestible substrate and the enteric
coating.
18. The orally-ingestible substrate of claim 17, wherein the
enteric coating comprises a partially neutralized enteric
polymer.
19. The orally-ingestible substrate of claim 18, wherein the
partially neutralized enteric polymer is a partially neutralized
methacrylic acid copolymer.
20. The orally-ingestible substrate of claim 19, wherein the
partially neutralized methacrylic acid copolymer comprises about 40
to 75% by weight of the enteric coating composition on a dry
basis.
21. An orally-ingestible substrate, substantially resistant to
disintegration in a pH 5.0 medium, comprising: i) a core portion
containing a drug or active ingredient; ii) an enteric coating
portion, substantially enveloping said core portion, the enteric
coating comprising a partially neutralized enteric polymer; and
iii) an acidifying topcoat substantially enveloping said enteric
coating portion.
22. The orally-ingestible substrate of claim 21, further comprising
a subcoat between the drug containing core and enteric coating
comprising a partially neutralized enteric polymer.
23. The orally-ingestible substrate of claim 21, wherein the
partially neutralized enteric polymer is a partially neutralized
methacrylic acid copolymer.
24. An orally-ingestible substrate of claim 21, wherein the core
portion comprises from about 50 to about 90% by weight; the enteric
coating portion comprises from about 8 to about 40% by weight and
the acidifying topcoat comprises from about 2 to about 30% by
weight.
25. The orally-ingestible substrate of claim 24, wherein the
acidifying topcoat comprises from about 3 to about 25% by
weight.
26. A method of preparing an orally-ingestible substrate which is
substantially resistant to disintegration in a pH 5.0 medium
comprising the steps of: i) providing a drug containing core; ii)
applying an enteric coating on the drug containing core; and iii)
applying an acidifying topcoat over the enteric coating.
27. The method of claim 26, further comprising the step of applying
a subcoat between the drug containing core and enteric coating.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority from U.S.
provisional application No. 62/656,611 filed Apr. 12, 2018, the
contents of which are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] This invention relates to the field of aqueous film coating
dispersions for coating pharmaceutical tablets and the like for pH
dependent release of the ingredients of coated tablets. It provides
a non-toxic, edible, dry powder composition for use in making an
aqueous coating dispersion that may be used as a topcoat for
pharmaceuticals with a pH dependent coating. The invention also
relates to pharmaceutical substrates having such film coatings,
which do not appreciably disintegrate in aqueous media of up to pH
5, and methods of preparing the same.
BACKGROUND OF THE INVENTION
[0003] U.S. Pat. No. 6,420,473 describes dry enteric film coating
compositions comprising an acrylic resin, an alkalizing agent, a
detackifier and, optionally, additional ingredients such as
plasticizers, flow aids, pigments, surfactants, anti-agglomerating
agents, secondary film formers and secondary detackifiers. Commonly
assigned U.S. Pat. No. 9,233,074 describes related dry enteric film
coating compositions which also advantageously include calcium
silicate for improved stability.
[0004] While the formulations disclosed in U.S. Pat. Nos. 6,420,473
and 9,233,074 are commercially useful, there is still a need for
improved enteric coated dosage forms that do not appreciably
disintegrate in media of up to pH 5.
SUMMARY OF THE INVENTION
[0005] It has been surprisingly found that by adding a topcoat
comprising one or more acidic components to an enteric-coated
dosage form, the top-coated dosage form has increased resistance to
disintegration in media with pH up to about 5.
[0006] In one aspect of the invention, there are provided dry
powder film coating compositions for the pharmaceutical and related
arts. The dry pH dependent film coating compositions include one or
more polymers, one or more acidic components and other additives
commonly used in film coating formulations.
[0007] In another aspect of the invention, there are provided
aqueous dispersions of the film coating compositions described
above. The dispersions preferably contain from about 5 to about 25%
non-water ingredients content. Still further aspects include
methods of coating orally-ingestible substrates with the coating
dispersions as well as the coated substrates prepared by these
methods, which have surprising resistance to disintegration in
media with pH up to about 5.
DETAILED DESCRIPTION OF THE INVENTION
[0008] For purposes of the present invention, the following terms
are given further clarification as to their meanings:
[0009] "orally-ingestible substrate" shall be understood to mean
any pharmaceutically acceptable dosage form, e.g. tablet, capsule,
caplet, drug-layered sugar spheres or similar beads, drug
particles, etc. or any other veterinary or confectionary product
capable of being taken via the oral route of administration;
[0010] "drug" shall be understood to include any biologically or
pharmaceutically recognized active ingredient, including
nutritional supplements whether organically synthesized, made by
recombinant techniques or natural extract;
[0011] "dry powder" shall be understood to mean powders which are
relatively dry to the touch rather than powders which are
essentially without liquid content;
[0012] "ambient temperature" shall be understood to mean
temperatures generally in the range of from about 20.degree. C.
(68.degree. F.) to about 30.degree. C. (86.degree. F.)+/-3.degree.
C.;
[0013] "pH dependent" shall be understood to mean a polymer or
coating that is soluble in one pH range but not in another. For
example, a traditional "enteric" polymer or coating is insoluble at
low pH, up to about 5 for example, but is soluble at higher pH i.e.
about 6.5 or greater; and
[0014] "substantially resistant to disintegration" with respect to
film coatings shall be understood to relate to film coatings which
when applied to a tablet, capsule or multi-particulate release less
than about 5% of an active ingredient coated therein within about 2
hours in an in vitro dissolution medium.
[0015] The acidifying film coating compositions comprise one or
more polymers, one or more acidic components, optionally one or
more plasticizers, and, in some cases, one or more optional
ingredients such as detackifiers, pigments, surfactants and the
like.
[0016] The polymer or polymers may be any of the polymers commonly
used in immediate release film coatings. Suitable polymers include
hypromellose (hydroxypropylmethyl cellulose or HPMC), hydroxypropyl
cellulose (HPC), sodium carboxymethyl cellulose, polyvinyl alcohol
(PVA), polyvinyl alcohol-polyethylene glycol graft copolymer, other
copolymers based on PVA and mixtures thereof. In most embodiments,
the total amount of polymer(s) included in the powder mixtures of
the present invention is from about 10 to about 90% by weight. In
some preferred embodiments, it ranges from about 25 to about 85%
and more preferably ranges from about 30 to about 80% by weight of
the dry coating composition.
[0017] The acidic component may be any pharmaceutically approved
acidic substance which bears an ionizable hydrogen capable of
displacing cations found on a partially neutralized enteric
polymer. Suitable acidic components include stearic acid, citric
acid, lactic acid and mixtures thereof. In most embodiments, the
total amount of acidic component(s) included in the powder mixtures
of the present invention is from about 5 to about 50% by weight. In
some preferred embodiments, it ranges from about 8 to about 45% by
weight of the dry coating composition. While not wishing to be
bound by any particular theory, it is believed that the ionizable
hydrogen ions from the acidic component displace cations found on
partially neutralized enteric polymers in the enteric coatings of
enteric-coated orally ingestible substrates. Advantageously, the pH
at which the enteric polymers disintegrate increases when the
cations on partially neutralized enteric polymers are replaced with
hydrogen ions. Partially neutralized enteric polymers are generally
preferred when preparing enteric coated dosage forms, since they
are much more readily dispersed in water than unneutralized forms.
So, the use of an acidifying topcoat improves the functionality of
preferred enteric coatings.
[0018] In those aspects of the invention where a plasticizer is
included in the acidifying coating compositions, the amount used is
dependent upon the plasticizer selected as well as the type and
amount of polymer included in the film coating composition. As will
be appreciated by those of ordinary skill, the amount of
plasticizer included is an amount which achieves sufficient
plasticization, i.e. improvement in the softening and/or lowering
of the glass transition temperature, of the polymer when the film
coating composition is in the form of an aqueous dispersion or in
the form of a coating on an orally-ingestible substrate. A
non-limiting list of suitable plasticizers includes triethyl
citrate, triacetin, medium chain triglycerides, glyceryl
caprylocaprate (also known as glyceryl mono and dicaprylocaprate),
polyethylene glycol having a molecular weight in the range of 200
to 8000 and glycerol. In most embodiments, the amount of
plasticizer is from about 0 to about 20% by weight of the polymer
content. In some preferred embodiments, it ranges from about 2 to
about 18% by weight of the polymer content.
[0019] A non-limiting list of suitable detackifiers include talc,
carnauba wax, hydrogenated castor oil, sodium stearyl fumarate
other or mixtures thereof and is used principally to reduce the
incidence of tablet sticking that can occur during the film coating
of pharmaceutical tablets and the like using aqueous dispersions
based on the inventive compositions. In most embodiments, the total
detackifier content is from about 0 to about 50% of the dry film
coating composition. In some preferred embodiments, it ranges from
about 5 to about 45% of the dry film coating composition.
[0020] Suitable pigments are those which are FD&C or D&C
lakes, titanium dioxide, calcium carbonate, iron oxides,
riboflavin, carmine 40, curcumin, annatto, other non-synthetic
colorants, insoluble dyes, pearlescent pigments based on mica
and/or titanium dioxide or mixtures thereof. The type and amount of
pigment used is dependent upon the desired color will be apparent
to those of ordinary skill. Multiple pigments may be used together
to create different varying color shades. The total amount of
pigment may range from 0 to about 40% by weight of the dry coating
composition. In some preferred embodiments, it ranges from about 5
to about 30% of the dry coating composition.
[0021] Suitable surfactants will be apparent to those of ordinary
skill. In many preferred aspects, however, the surfactant is sodium
lauryl sulfate. The surfactant is used principally to reduce the
surface tension of the aqueous dispersion prepared from the
inventive dry coating composition. The surfactant facilitates
droplet spreading and, correspondingly, coating uniformity. In most
embodiments, the amount of surfactant used is between 0 and about
5% of the weight of the film coating composition. In some preferred
embodiments, it ranges from about 0.1 to about 4% by weight of the
composition.
[0022] Furthermore, the powder mixtures may also include
supplemental or auxiliary ingredients typically found in film
coatings. A non-limiting list of such adjuvants includes dispersion
aids, sweeteners, flavorants, etc. and mixtures thereof.
[0023] While it is often more advantageous and economical to
incorporate as many of the benefit imparting additives into the dry
coating composition prior to preparing the aqueous dispersion, it
is also possible to add the ingredients stepwise to the aqueous
dispersion. For example, one could initially disperse a mixture of
polymer and acidic agent in an aqueous medium and then add stepwise
the plasticizer, detackifier, surfactant and pigment. Furthermore,
an anti-foaming agent may be added directly to the aqueous
dispersion, if desired, as well.
[0024] The powder mixtures are prepared using standard dry blending
or mixing techniques known to those of ordinary skill. For example,
the ingredients are individually weighed, added to a suitable
apparatus and blended for a sufficient time until a substantially
uniform mixture of the ingredients is obtained. The time required
to achieve such substantial uniformity will, of course, depend upon
the batch size and apparatus used. If any of the powder formulation
ingredients are liquids, they are added only after all of the dry
ingredients have been sufficiently blended, and the combination of
wet and dry ingredients is blended for an additional amount of time
to ensure homogeneity once all of the liquid is introduced.
[0025] In certain embodiments, it is preferable to blend two or
more ingredients together as a dry pre-blend. For example, a
pre-blend of a liquid acidic component such as lactic acid and a
portion of the polymer such as hypromellose can be produced on a
large scale. The resulting free-flowing powders can then be stored
and subsequently used in the production of multiple batches of
fully-formulated coating compositions. Another exemplary pre-blend
is the combination of talc and lactic acid. Advantageously, the
pre-blends can be added quickly to the remaining dry ingredients
including the remainder of the polymer, detackifier, plasticizer
and pigments, thereby eliminating the need for additional blending
time to disperse a liquid component.
[0026] As mentioned above, batch sizes will vary upon need. A
non-limiting list of suitable blending devices include diffusion
blenders such as a cross flow, V-blender, or hub blender, available
from Patterson-Kelly, or convection blenders, such as Ruberg or CVM
blenders, available from Azo, Servolift and Readco. Blending of the
aforementioned formulations may also be achieved by processing
ingredients into a granular form to produce a non-dusting granular
coating composition by methods including, but not limited to, wet
massing, fluid bed granulation, spray granulation and dry
compaction, roller compaction or slugging. Other manners of
blending will be apparent to those of ordinary skill.
[0027] The enteric-coated dosage forms to which the acidifying
topcoats are applied are comprised of drug-containing cores and an
enteric coating. It is also often advantageous to include a subcoat
between the drug-containing core and the enteric coating to provide
greater physical strength to the core and also to minimize
potential interactions between the components of the core and
enteric coating. The enteric coating comprises a pH dependent
polymer (also known as an enteric polymer). Suitable pH dependent
polymers include polyvinylacetate phthalate, hydroxypropylmethyl
cellulose acetate succinate, hydroxypropylmethyl cellulose
phthalate, cellulose acetate phthalate and methacrylic acid
copolymers. Preferred methacrylic acid copolymers include:
poly(methacrylic acid, methyl methacrylate) 1:1 sold, for example,
under the Eudragit L100 trade name; poly(methacrylic acid, ethyl
acrylate) 1:1 sold, for example, under the Eudragit L100-55 or
Kollicoat MAE 100-55 trade names; and poly(methacrylic acid, methyl
methacrylate) 1:2 sold, for example, under the Eudragit S100 trade
name. A non-limiting list of commercially available, ready to use
enteric polymer film coatings suitable for use in connection with
the invention described herein include those available from
Colorcon, under the tradenames AcrylEZE.RTM., Nutrateric.RTM. and
Sureteric.RTM..
[0028] As previously mentioned, enteric polymers are often
partially neutralized to facilitate dispersion in water. Suitable
alkalizing agents (or neutralizing agents) for the enteric polymers
include, for example, sodium bicarbonate, potassium bicarbonate and
ammonium carbonate. Each of the foregoing as well as those known to
those of ordinary skill not specifically mentioned herein, are
useful in compositions that comprise pH dependent, enteric polymers
that have not been pre-neutralized. Sodium bicarbonate is an
especially preferred alkalizing agent. The quantity of alkalizing
agent used is directly dependent on the amount of carboxylic
acid-bearing monomer present in the pH dependent polymer.
Specifically, the alkalizing agent is added in a quantity such
that, after reaction with the pH dependent, enteric polymer, 0.1 to
10 mole percent of the acidic groups are present in the salt form.
In cases where the carboxylic acid groups on a polymer have been
pre-neutralized prior to use, as is the case with
partially-neutralized poly(methacrylic acid, ethyl acrylate) 1:1
sold under the Kollicoat MAE-100P trade name, the use of an
alkalizing agent in the enteric film coating composition is not
necessary, since the pre-neutralized polymer is already
dispersible.
[0029] Enteric-coated dosage forms are prepared consistent with
current industry practices and as disclosed in U.S. Pat. Nos.
6,420,473 and 9,233,074, the contents of each of which are
incorporated herein by reference. Preferably, aqueous film coating
processes are used to apply enteric coatings to drug-containing
cores. The amount of enteric coating applied depends on the surface
area of the core. For example, tablets generally require about
8-10% weight gain; whereas, beads or spheres, with larger surface
areas, generally require 30-40% weight gain.
[0030] The enteric-coated, orally-ingestible substrates described
above can also include a subcoat film coating between the
orally-ingestible substrate and the inventive film coating
composition. The subcoat selected is preferably based on an edible
film coating composition that is compatible with and adheres to
both the drug-containing core and the enteric coating. Thus, the
artisan may choose from a wide variety of pharmaceutical or
food-acceptable coatings for use as subcoats in the present
invention. The subcoat is also applied to the substrate to provide
from about a 0.25 to about a 10% weight gain to the enteric-coated,
orally-ingestible substrate.
[0031] Acidifying topcoat dispersions are prepared by adding the
premixed, dry powder acidifying coating composition to deionized
water with continuous stirring at ambient temperature. In most
embodiments, 5 to 25 parts of the premixed, dry powder acidifying
coating composition are added to 75 to 95 parts of deionized water.
In preferred embodiments, 10 to 20 parts of the premixed, dry
powder acidifying coating composition are added to 80 to 90 parts
of deionized water. The resulting acidifying coating dispersion is
then sprayed onto enteric-coated, orally-ingestible substrates
using commercial film coating equipment known to those skilled in
the art. In most embodiments, the acidifying topcoats are applied
such that 2-30% weight gain with respect to the starting weight of
the enteric-coated substrates is achieved. The preferred amount of
acidifying topcoat increases with increasing surface area of the
enteric-coated substrates. For tablets and capsules, the acidifying
topcoats are preferably applied such that 3-8% weight gain with
respect to the starting weight of the enteric-coated tablets and
capsules is achieved. For multiparticulates or beads, the
acidifying topcoats are preferably applied such that 3-25% weight
gain with respect to the starting weight of the enteric-coated
multiparticulates or beads is achieved.
[0032] In accordance with certain embodiments, the orally
ingestible substrates, which include tablets and multiparticulates,
can have a plurality of layers. For example, in the center portion
there is a core which can contain a drug or active ingredient. The
enteric coating layer or portion substantially envelops the core
and the acidifying topcoat portion substantially envelops the
enteric coating layer. There can be an optional subcoat separating
the enteric coating and the core, which does not substantially
affect the property of the final product being substantially
resistant to disintegration in a pH 5.0 medium.
[0033] The core portion can comprise from about 50 to about 90% by
weight of the final product/substrate while the enteric coating
portion can comprise from about 8 to about 40% by weight and the
acidifying topcoat comprises from about 2 to about 30% by weight.
In a further aspect, the acidifying topcoat comprises from about 3
to about 25% by weight.
[0034] Some preferred dry acidifying topcoat compositions in
accordance with the present invention include:
TABLE-US-00001 % by weight of the composition More Ingredient
(unless otherwise noted) Preferred Preferred Polymer 10-90 25-85
30-80 Acidic component 5-50 8-45 -- Plasticizer (% by 0-20 2-18 --
weight of the polymer) Detackifier 0-50 5-45 -- Pigments 0-40 5-30
-- Surfactant 0-5 0.1-4 -- (sodium lauryl sulfate) Other auxiliary
0-20 -- -- ingredients
[0035] It will be understood from the foregoing table that the
preferred dry film coating compositions will include at least a
polymer and an acidic component as described herein. The additional
ingredients, if included, will cause the amount of polymer and
acidic component to be reduced but still within the ranges
described herein so that the total amount of all ingredients in the
dry blend will be 100% by weight.
[0036] For purposes of illustration and not limitation, an aqueous
acidifying topcoat dispersion having about 10% solids content can
be formed by dispersing 40 grams of a blended powder mixture
described hereinabove into 360 grams of ambient temperature water.
The water is weighed into a suitable vessel, i.e. one with a
diameter approximately equal to the depth of the final dispersion.
A low shear mixer, preferably one having a mixing blade with a
diameter about one third the diameter of the mixing vessel, is
lowered into the water and turned on to create a vortex from the
edge of the vessel down to about just above the mixing blade to
prevent entrapment of air. The 40 grams of dry film coating
composition is added to the vortex at a rate where there is no
excessive buildup of dry powder. The speed and depth of the mixing
blade is adjusted to avoid air being drawn into the dispersion so
as to avoid foaming. The dispersion is stirred at low speed,
preferably 350 rpm or less, for a time sufficient to ensure that a
homogenous mixture is formed. Using the above batch size as a
guide, about 45 minutes mixing time is required. The dispersion is
then ready for spraying onto pharmaceutical substrates and the
like. Those of ordinary skill will also realize that there are many
ways of preparing a substantially homogenous mixture of the solids
in water and that the scope of the invention is in no way dependent
on the apparatus used.
[0037] As mentioned previously, it is also possible to add the
optional ingredients stepwise to the aqueous dispersion. For
example, one could initially disperse a polymer, acidic component
and plasticizer in an aqueous medium and then add stepwise
detackifier, surfactant and pigment using the same equipment as
described above.
[0038] In still further embodiments of the invention, there are
provided enteric-coated, orally-ingestible substrates coated with
the inventive acidifying topcoat formulations. In some preferred
embodiments, the enteric polymer in the enteric coating comprises
partially-neutralized methacrylic acid copolymer. In additional
preferred embodiments, the amount of enteric polymer in the enteric
coating composition is from about 40 to 75% by weight of the
enteric coating composition and more preferably 55-70%. The coated
substrates have excellent appearance and uniformity, resistance to
agglomeration and desirable delayed release properties.
[0039] As will be described in the examples below, the methods
include applying the acidifying topcoat coating compositions as
aqueous dispersions to the surfaces of orally ingestible
substrates. The acidifying topcoat can be applied as part of a pan
coating or spray coating process commonly used to coat such
articles. The amount of coating applied will depend upon several
factors, including the composition of the coating, the substrate to
be coated and the apparatus employed to apply the coating, etc. In
most embodiments, the acidifying topcoats are applied such that
2-30% weight gain with respect to the starting weight of the
enteric-coated substrates is achieved. In preferred embodiments,
the acidifying topcoats are applied such that 3-25% weight gain
with respect to the starting weight of the enteric-coated
substrates is achieved.
[0040] A non-limiting list of suitable substrates that can be
coated with the inventive coating system include compressed
tablets, caplets, cores including pharmaceuticals, drug-layered
sugar spheres or similar beads, nutraceuticals and dietary
supplements as well as any other art-recognized, orally-ingestible
core.
EXAMPLES
[0041] The following examples serve to provide further appreciation
of the invention but are not meant in any way to restrict the
effective scope of the invention. All ingredients are expressed as
being by weight %.
Example 1
[0042] Preparation of Enteric Coated Placebo Tablets
[0043] I. Preparation of Placebo Tablets
[0044] Round, biconvex placebo tablets (11 mm diameter) were
prepared by compressing a dry-blended mixture of lactose
monohydrate (42 parts), microcrystalline cellulose (42 parts),
Starch 1500 (15 parts), colloidal silicon dioxide (0.5 parts) and
magnesium stearate (0.5 parts) on a Piccola 10-station,
instrumented tablet press.
[0045] II. Preparation of Subcoat and Enteric Coating
Dispersions
[0046] The placebo tablets were coated sequentially with a
sub-coating dispersion made from an Opadry.RTM. coating composition
based on hypromellose (HPMC) and an enteric coating dispersion
prepared in accord with the compositions described in U.S. Pat. No.
9,233,074. First, the Opadry sub-coating dispersion was prepared by
adding the dry Opadry formula (75 grams) to deionized water (607
grams) and stirring this combination with a propeller mixer for 45
minutes. A homogeneous dispersion was thus obtained.
[0047] An enteric coating dispersion was prepared by adding a
premixed, dry powder enteric composition to water. The dry powder
enteric composition was prepared by thoroughly mixing Eudragit.RTM.
L100-55 (137.5 grams; 55.0 wt %), sodium bicarbonate (2.8 grams;
1.1 wt %), talc (49.5 grams; 19.8 wt %), titanium dioxide (32.5
grams; 13.0 wt %), poloxamer 407 (16.5 grams; 6.6%), calcium
silicate (10.0 grams; 4.0 wt %) and sodium lauryl sulfate (1.3
grams; 0.5 wt %) in a food processor for five minutes. A
free-flowing powder with no visible agglomerates was obtained. An
enteric dispersion was then prepared by first mixing an aqueous
silicon emulsion (Anti-foam FG-10; 0.5 gram) into deionized water
(1.0 kg) using a low shear mixer, having a mixing blade with a
diameter about one third the diameter of the mixing vessel, lowered
into the water and turned on to create a vortex from the edge of
the vessel down to about just above the mixing blade to prevent
entrapment of air. After mixing the anti-foam for 30 seconds, the
pre-mixed, dry powder enteric composition (250 grams) was added to
the vortex at a rate where there was no excessive buildup of dry
powder. The speed and depth of the mixing blade was adjusted to
avoid air being drawn into the dispersion so as to avoid foaming.
The dispersion was stirred at low speed, 350 rpm or less, for a
time sufficient to ensure that a homogenous mixture was formed.
About 45 minutes mixing time was required.
[0048] III. Coating of the Placebo Tablets with Subcoat and Enteric
Coating Dispersions
[0049] To a 24-inch diameter O'Hara LabCoat 2 coating pan, equipped
with internal peristaltic pump delivery system with two pump heads,
platinum-cured silicone tubing (size 16) and two Schlick spray guns
(model #301-246; fluid nozzle--(1 mm) 301-224 (12); air
cap--301-001) were added the placebo cores described previously (16
kg total charge). The tablets were subcoated with the Opadry
sub-coating dispersion under the following process conditions:
[0050] Coating Process Parameters (24'' O'Hara LabCoat 2)
TABLE-US-00002 Subcoat Fluid delivery rate (g/min) 60 Atomizing air
pressure (psi) 20 Pattern air pressure (psi) 20 Tablet bed
temperature (.degree. C.) 43 Pan speed (RPM) 12 Theoretical weight
gain (%) 4
[0051] No tackiness or tablet-to-tablet sticking was observed
during the coating run.
[0052] To a 15-inch diameter O'Hara LabCoat 1 coating pan, equipped
with a Masterflex L/S 7528-30 peristaltic pump with one pump head,
platinum-cured silicone tubing (size 15) and one Schlick spray gun
(Model #970/7-1S75; fluid nozzle--(1 mm) w44019; air cap--27
w44183) were added subcoated placebo cores (2.5 kg total charge).
The tablets were enteric coated with the enteric dispersion under
the following process conditions:
[0053] Coating Process Parameters (15'' O'Hara LabCoat 1)
TABLE-US-00003 Enteric Coat Fluid delivery rate (g/min) 23
Atomizing air pressure (psi) 18 Pattern air pressure (psi) 18
Tablet bed temperature (.degree. C.) 32 Pan speed (RPM) 18
Theoretical weight gain (%) 10
[0054] IV Preparation and Coating of an Acidifying Topcoat
Dispersion
[0055] An inventive acidifying topcoat was first prepared as a dry
powder premixed composition by thoroughly mixing hypromellose E6
(35 parts), hypromellose E15 (20 parts) and citric acid monohydrate
(40 parts) in a food processor for five minutes. To this solid
mixture was added glyceryl caprylocaprate (5 parts). After an
additional two minutes of mixing, a homogeneous, free-flowing
powder with no visible agglomerates was obtained.
[0056] A coating dispersion was prepared by gradually adding 32
parts of the acidifying topcoat to 288 parts of water with
continuous stirring. A homogenous dispersion was prepared in 30
minutes.
[0057] The acidifying topcoat dispersion was coated onto the
previously described enteric coated tablets using the following
coating process parameters:
[0058] Coating Process Parameters (10'' O'Hara LabCoat 1)
TABLE-US-00004 Acidifying Topcoat Fluid delivery rate (g/min) 4
Atomizing air pressure (psi) 10 Pattern air pressure (psi) 15
Tablet bed temperature (.degree. C.) 47 Pan speed (RPM) 22
Theoretical weight gain (%) 3, 4
[0059] Coated tablet samples were taken when 3% and 4% weight gain
of the acidifying topcoat was applied.
[0060] Testing of the Enteric Coated Tablets with and without
Acidifying Topcoat
[0061] To evaluate resistance to pH 5.0 media, 6 coated tablets
were individually weighed and placed in a pH 5.0 acetate buffer for
2 hours in a disintegration bath (Erweka ZT44), after which they
were removed and inspected for bloating, cracking, discoloration
and premature disintegration. Tablets were dried using a tissue
paper and reweighed. The average percent weight difference, before
and after immersion in the disintegration medium, was reported as
the fluid uptake value. A passing result was assigned if the tablet
coatings remained intact, and the tablets did not disintegrate. The
results were as follows:
TABLE-US-00005 % Fluid uptake in pH Sample 5.0 Acetate Buffer
Enteric coated tablets from Example 1 Failed; all tablets cracked
(no acidifying topcoat applied) and disintegrated Tablets with
acidifying topcoat Passed; 16.2% from Example 2 (3% weight gain)
Tablets with acidifying topcoat Passed; 11.2% from Example 2 (4%
weight gain)
Examples 2-4
[0062] Dry powder acidifying topcoats were prepared, subsequently
dispersed in aqueous media and coated onto enteric coated placebos
as described in Example 1, with an additional 5% weight gain sample
obtained. The resulting coated tablets were subjected to
disintegration testing, also as described in Example 1. The
formulations and results are reported in the following table.
TABLE-US-00006 Weight % Components Example 2 Example 3 Example 4
Hypromellose E6 80 60 70 Citric acid monohydrate -- 30 20 Stearic
acid 20 10 10 100 100 100 Tablet appearance and % fluid uptake
after 2 hours in pH 5.0 acetate buffer (n = 6) 3% weight gain
Passed; Passed; Passed; 9.2% 11.5% 10.2% 4% weight gain Passed;
Passed; Passed; 7.0% 9.0% 7.9% 5% weight gain Passed; Passed;
Passed; 6.5% 6.6% 7.0%
Examples 5-7
[0063] Dry powder acidifying topcoats were prepared, subsequently
dispersed in aqueous media and coated onto enteric coated placebos
as described in Example 1. The resulting coated tablets were
subjected to disintegration testing, also as described in Example
1. The formulations and results are reported in the following
table.
TABLE-US-00007 Weight % Components Example 5 Example 6 Example 7
Hypromellose E6 80 85 85 Citric acid monohydrate 10 5 -- Lactic
acid (90% in water) -- -- 10 Stearic acid 10 10 5 100 100 100
Tablet appearance and % fluid uptake after 2 hours in pH 5.0
acetate buffer (n = 6) 3% weight gain Passed; Passed; Passed; 8.7%
31.0% 5.5% 4% weight gain Passed; Passed; Passed; 7.9% 6.3% 3.9% 5%
weight gain Passed; Passed; Passed; 5.0% 4.9% 2.7%
Examples 8-9
[0064] Enteric-coated placebo tablets were prepared as described in
Example 1 except that the enteric coating formulation had 65%
enteric polymer rather than 55% enteric polymer. The dry powder
enteric composition contained Eudragit.RTM. L100-55 (130 grams;
65.0 wt %), sodium bicarbonate (1.43 grams; 0.715 wt %), talc
(52.17 grams; 26.085 wt %), poloxamer 407 (10.4 grams, 5.2 wt %),
calcium silicate (5 grams; 2.5 wt %) and sodium lauryl sulfate (1
gram; 0.5 wt %).
[0065] Dry powder acidifying topcoats were prepared, subsequently
dispersed in aqueous media and coated onto enteric coated placebos
to 3% weight gain as described in Example 1. The resulting coated
tablets were subjected to disintegration testing, also as described
in Example 1. The formulations and results are reported in the
following table.
TABLE-US-00008 Weight % Components Example 8 Example 9 Hypromellose
E6 48.89 65 Lactic acid (90%) 11.11 Stearic acid 10 Talc 40
Microcrystalline Cellulose 10 TiO2 15 100 100 Tablet appearance and
% fluid uptake after 2 hours in pH 5.0 acetate buffer (n = 6) 3%
weight gain Passed; Passed; 2.02% 1.54%
[0066] Significantly lower media uptake was observed when the
enteric polymer concentration in the enteric coating was increased
from 55 to 65%.
Example 10
[0067] Suglets.RTM. sugar spheres were drug layered with
lansoprazole and sequentially sub-coated with a dispersion made
from an Opadry.RTM. coating dispersion based on hypromellose
(HPMC), an enteric coating dispersion, and finally an acidifying
topcoat.
[0068] To a Huttlin Unilab fluid bed coater, equipped with a
Discjet plate, internal peristaltic pump with two heads (Watson
Marlow), silicone tubing (Masterflex 96410-16) and two Huttlin
spray guns (1 mm fluid nozzles) were added 5 kg Suglets.RTM. sugar
spheres 18/20 mesh (1000/850 micron size). A lansoprazole drug
layer coating dispersion was prepared by adding and thoroughly
mixing Opadry.RTM. (187.5 grams), sodium bicarbonate (75 grams) and
lansoprazole (75 grams) into deionized water (1912.5 grams) using a
low shear mixer for a time sufficient to ensure that a homogenous
mixture was formed. About 45 minutes mixing time was required.
[0069] The lansoprazole drug layered spheres (5.0 kg) were then
coated with an Opadry.RTM. sub-coat dispersion (250 grams Opadry in
2250 kg deionized water) in a Huttlin Unilab fluid bed coater. A
portion of these subcoated spheres (500 grams) were then coated
with an enteric coating dispersion (175 grams dry enteric coating
premix in 700 grams deionized water in an Aeromatic Strea-2 fluid
bed coater with Wurster insert. The process conditions used for the
three coating steps were:
[0070] Coating Process Parameters (Huttlin Unilab Fluid Bed)
TABLE-US-00009 Lansoprazole Drug Coat SubCoat Fluid delivery rate
(g/min) 10 11 Atomizing air pressure (bar) 1.7 1.7 Air velocity
(m.sup.3/h) 500 500 Product temperature (.degree. C.) 47 45
[0071] Coating Process Parameters (Aeromatic Strea-2 Fluid Bed)
TABLE-US-00010 Enteric Coat Fluid delivery rate (g/min) 5 Atomizing
air pressure (bar) 1.6 Air velocity (m.sup.3/h) 130 Product
temperature (.degree. C.) 36
[0072] The enteric-coated beads so obtained were then coated with
an acidifying topcoat. The topcoat was first prepared as a dry
powder premix by mixing hypromellose E6 (85 parts), lactic acid
(90% in water; 11 parts) and stearic acid (5 parts). The dry powder
premix (20 parts) was added to deionized water (180 parts) and
stirred with a propeller stirrer for 60 minutes. The acidifying
topcoat dispersion was then coated onto the enteric-coated beads
until a 4% weight gain was achieved according to the following
process conditions:
[0073] Coating Process Parameters (Aeromatic Strea-2 Fluid Bed)
TABLE-US-00011 Acidifying Topcoat Fluid delivery rate (g/min) 3
Atomizing air pressure (bar) 1.6 Air velocity (m.sup.3/h) 130
Product temperature (.degree. C.) 46
[0074] Enteric-coated multiparticulates, with and without an
acidifying topcoat, were evaluated by using a modified version of
USP Dissolution Method <711> according to the
"delayed-release" lansoprazole monograph. Three separate one-gram
samples of the coated multiparticulates were placed in pH 5.0
acetate buffer (1 L) for two hours at 37.degree. C. using apparatus
1 at 75 RPM. The amount of the drug released in this medium was
tested after 1 and 2 hours by taking half of each sample and
analyzing it at the given time point. The following data were
obtained:
TABLE-US-00012 Sample % Lansoprazole Released Enteric coated
spheres (no acidifying topcoat) 1 hr @ pH 5.0 42.7 2 hr @ pH 5.0
51.3 Enteric coated spheres (4% weight gain acidifying topcoat) 1
hr @ pH 5.0 8.3 2 hr @ pH 5.0 12.8
Example 11
[0075] Suglets.RTM. sugar spheres were drug layered and sub-coated
similarly as in example 10 except chlorpheniramine maleate (CPM)
was used as the active. To a Huttlin Unilab fluid bed coater, 7650
g of the sugar spheres were loaded. A CPM drug layer coating
dispersion was prepared by adding and thoroughly mixing Opadry.RTM.
(122.4 grams) and CPM (286.9 grams) into deionized water (2319.2
grams) using a low shear mixer for a time sufficient to ensure that
a homogenous mixture was formed. About 45 minutes mixing time was
required.
[0076] The CPM drug layered spheres (7.5 kg) were then coated with
an Opadry.RTM. sub-coat. The Opadry.RTM. sub-coat coating
dispersion was prepared by adding and thoroughly mixing Opadry.RTM.
(37.5 grams) into deionized water (431.3 grams) using a low shear
mixer for a time sufficient to ensure that a homogenous mixture was
formed. About 45 minutes mixing time was required.
[0077] A portion of the sub-coated CPM sugar spheres (500 grams)
were then coated with an enteric coating dispersion in an Aeromatic
Strea-2 fluid bed coater with Wurster insert. The enteric coating
dispersion was prepared by adding a premixed, dry powder enteric
composition to water. The dry powder enteric composition was
prepared by thoroughly mixing Eudragit.RTM. L100-55 (113.75 grams;
65.0 wt %), sodium bicarbonate (1.25 grams; 0.715 wt %), talc
(45.65 grams; 26.085 wt %), poloxamer 407 (9.1 grams, 5.2 wt %),
calcium silicate (4.38 grams; 2.5 wt %) and sodium lauryl sulfate
(0.88 gram; 0.5 wt %) in a food processor for five minutes. A
free-flowing powder with no visible agglomerates was obtained. An
enteric dispersion was then prepared by first mixing a simethicone
anti-foam emulsion (Dow Corning DC Q7-2243; 0.88 gram) into
deionized water (431.3 grams) using a low shear mixer for a time
sufficient to ensure that a homogenous mixture was formed. About 45
minutes mixing time was required. The conditions for the three
coatings processes were:
[0078] Coating Process Parameters (Huttlin Unilab Fluid Bed)
TABLE-US-00013 CPM Drug Coat SubCoat Fluid delivery rate (g/min) 6
6 Atomizing air pressure (bar) 1.7 1.7 Air velocity (m.sup.3/h) 300
400 Product temperature (.degree. C.) 47 47
[0079] Coating Process Parameters (Aeromatic Strea-2 Fluid Bed)
TABLE-US-00014 Enteric Coat Fluid delivery rate (g/min) 4.7
Atomizing air pressure (bar) 1.8 Air velocity (m.sup.3/h) 130
Product temperature (.degree. C.) 35
[0080] The enteric-coated beads so obtained were then coated with
an acidifying topcoat. The topcoat was first prepared as a dry
powder premix by mixing hypromellose E6 (48.89 parts), lactic acid
(90% in water; 11.11 parts) and talc (40 parts). The dry powder
premix (16 parts) was added to deionized water (144 parts) and
stirred with a propeller stirrer for 60 minutes. The acidifying
topcoat dispersion was then coated onto the enteric-coated beads
until a 4% weight gain was achieved according to the following
process conditions:
[0081] Coating Process Parameters (Aeromatic Strea-2 Fluid Bed)
TABLE-US-00015 Acidifying Topcoat Fluid delivery rate (g/min) 2.4
Atomizing air pressure (bar) 1.9 Air velocity (m.sup.3/h) 130
Product temperature (.degree. C.) 43
[0082] Enteric-coated multiparticulates, with and without an
acidifying topcoat, were evaluated by using a modified version of
USP Dissolution Method <711> according to the
chlorpheniramine maleate extended release monograph. Two separate
one-gram samples of the coated multiparticulates were placed in pH
5.0 acetate buffer (1 L) for two hours at 37.degree. C. using
apparatus 1 at 75 RPM. The amount of the drug released in this
medium was tested after 1 and 2 hours by taking half of each sample
and analyzing it at the given time point. The following data were
obtained:
TABLE-US-00016 Sample % CPM Released Enteric coated spheres (no
acidifying topcoat) 1 hr @ pH 5.0 15.4 2 hr @ pH 5.0 32.2 Enteric
coated spheres (4% weight gain acidifying topcoat) 1 hr @ pH 5.0
1.23 2 hr @ pH 5.0 2.22
* * * * *